Highlights from Recent Cancer Literature
Journal: Cancer Research (2011)

Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 2011;71:1263–71.The immune system plays a complex role as both a barrier and instigator of tumorigenesis. A key challenge has been to translate this insight into clinically useful information. Tosolini and colleagues have performed a detailed analysis of the roles of different immune effectors on the pathogenesis of colorectal cancer. They analyzed a panel of 125 frozen colon carcinoma samples for mRNAs associated with regulation of immune effector pathways. Hierarchical clustering enabled identification of mRNAs suggestive of cytotoxic T cells, T regulatory cells, T helper (Th)1, and Th17 cells. Those mRNAs in the Th17 gene cluster were associated with poor prognosis, whereas mRNAs in the Th1 cluster were associated with a favorable prognosis. Moreover, multivariate analysis for both clusters enhanced the ability to predict clinical outcome. These results highlight the significance of gene expression cluster analysis for evaluating complexity and the potential use of immune “signatures” as predictors of clinical outcome and response to therapy.Godefroy E, Manches O, Dréno B, Hochman T, Rolnitzky L, Labarrière N, et al. Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory T(H)2 cells via an IL-12- and OX40L-dependent pathway. Cancer Cell 2011;19:333–46.The dogma suggests that matrix metalloproteinases (MMP) are important for tissue remodeling and cancer cell metastasis. However, immunotherapists working with melanoma patients have appreciated that MMP-2 also represents a melanoma associated antigen (MAA) of some significance. In fact, adoptive transfer of CD8+ T cells recognizing MMP-2 in a subset of cancer patients has led to durable tumor repression for up to 15 years. Approximately 40% of tumor-infiltrating leukocytes (TIL) isolated from melanomas represent MMP-2–specific CD4+ cells. Because CD4+ cells are important for generating effective antitumor responses, Godefroy and colleagues set out to characterize MMP-2–specific CD4+ T cells, the mechanisms by which they are generated, and their biological significance. Using both TILs and lymphocytes from normal donors, they uncovered an intriguing and important mechanism by which active MMP-2 acts as a conditioner for T-helper (Th)2 responses contributing to the immune-suppressive microenvironment of melanomas. Specifically, they found that CD4+ T cells secrete a range of Th2 cytokines, including interleukin (IL)-4, TNF-α, and IL-13, and express the transcription factor GATA3. Moreover, dendritic cells conditioned by active MMP-2 are able to polarize naïve CD4+ T cells to an inflammatory Th2 phenotype through OX40 ligand expression and inhibition of IL-12p70 production. Because MMP-2 also degrades the type I IFN receptor, thereby preventing STAT1 phosphorylation, induction of the p35 component of IL-12 is also prevented. Many MAAs have been identified, and several of them represent targets for immunotherapy. However, efficacy of these treatments is limited due to immunosuppressive factors in the tumor microenvironment, exhaustion/elimination of T cells by malignant cells, and immune escape of some malignant clones. Because active MMP-2 has a broad conditioning role in stimulating tumor-promoting Th2 responses in melanoma and many patients already have some T-cell clones that recognize the antigen, MMP-2 is a promising target antigen in melanoma that may help improve antitumor Th1 responses in this challenging disease.Winslow MM, Dayton TL, Kim-Kiselak C, Snyder EL, Feldser DM, Hubbard DD, et al. Suppression of lung adenocarcinoma progression by NKX2-1. Nature 2011 Apr 6; [Epub ahead of print].Lung cancer remains among the most common and deadly of cancers. To identify genes that contribute to malignant progression, Winslow and colleagues used a genetically engineered mouse model for adenocarcinoma driven by KRAS and p53 loss. Comparing metastatic and nonmetastatic lesions and integrating similar expression data from human lung cancer, they identified the homeobox transcription factor NKX2-1 as a tumor suppressor that regulates both differentiation and metastasis. Mechanistically, NKX2-1 acts in part by repressing the chromatin regulator Hmga2. NKX2-1 had been previously identified as being amplified and oncogenic in a subset of lung cancers. These data therefore suggest that NKX2-1 is both an oncogene and a tumor suppressor gene in lung cancer.Wang Y, Liu Y, Malek SN, Zheng P, Liu Y. Targeting HIF1α eliminates cancer stem cells in hematological malignancies. Cell Stem Cell 2011;8:399–411..The stem cell hypothesis posits that cancer stem cells are drivers of cancer, and that elimination of these cells is critical to our ability to “cure” cancer. But how do we target cancer stem cells? Wang and colleagues identify hypoxia-inducible factor (HIF1α) as activated in mouse lymphoma and in samples of human acute myeloid leukemia (AML). HIF1α maintained cancer stem cells in the mouse by repressing a negative feedback loop driven by Notch signaling. Echinomycin, a small molecule inhibitor of HIF1, eliminated cancer stem cells and eradicated serially transplantable human AML, suggesting that HIF1α may represent a target for blocking cancer stem cell function in hematologic malignancies.Li W, Li F, Huang Q, Shen J, Wolf F, He Y, et al. Quantitative, noninvasive imaging of radiation-induced DNA double strand breaks in vivo. Cancer Res; Published OnlineFirst April 28, 2011; doi:10.1158/0008-5472.CAN-10-2540.DNA double-strand breaks (DSB) are a major form of DNA damage caused by ionizing radiation and a primary mechanism through which radiotherapy and specific chemotherapeutic agents kill cancer cells. The conventional way of monitoring DSBs involves gel electrophoresis or immunofluorescence staining. In a recent article, Li and colleagues describe an interesting approach that permits noninvasive visualization of DSBs in vivo through bi-fragment luciferase reconstruction. This approach involves fusing N- and C-terminal fragments of firefly luciferase genes to the H2AX and MDC1 genes, respectively. At the sites of DSBs, the H2AX protein is phosphorylated and physically associates with the MDC1 protein, thus allowing the N- and C- luciferase fragments to join and reconstitute luciferase activity. This approach permitted serial noninvasive quantification of DSBs in cells irradiated with X-rays and 56Fe ions and noninvasive visualization of DSBs in vivo in irradiated tumors over a 2-week period. A few surprises emerged from this study, including a second wave of DSB induction in irradiated tumor cells that occurred days after radiation, which was evident in addition to the initial rapid induction of DSBs. This split-luciferase method for imaging γ-H2AX-MDC1 interactions is potentially useful for noninvasive imaging of DSBs in vivo, particularly when temporal studies are being performed over an extended period of time.Eskiocak U, Kim S, Ly P, Roig A, Biglione S, Komurov K, et al. Functional parsing of driver mutations in the colorectal cancer genome reveals numerous suppressors of anchorage-independent growth. Cancer Res; Published OnlineFirst April 28, 2011; doi:10.1158/0008-5472.CAN-11-0794.Loss of anchorage dependence is a hallmark of transformation of epithelial cells and directly correlates with tumorigenic potential. The precise mechanism underlying this switch in phenotype as a normal epithelial cell becomes a malignant cell is an area of intense investigation. Recent approaches using RNA interference have permitted loss-of function screens identifying potential tumor suppressors in mammalian cells. These studies have suggested that specific tumor suppressors may function in a cell context-specific manner, indicating that screens need to be used to evaluate multiple tissue types to obtain a clear appreciation of the spectrum of potential suppressors. In an interesting study, Eskiocak and colleagues used anchorage independence as an end point with short hairpin RNA (shRNA) screens to functionally interrogate candidate colorectal cancer genes (CAN-genes) to identify driver tumor-suppressors. The authors used an isogenic human colonic epithelial cell (HCEC) model to identify suppressors of anchorage-independent growth through a soft agar-based shRNA screen within the cohort of CAN-genes. Interestingly, depletion of 65 of the 151 CAN-genes tested cooperated with ectopic expression of K-rasv12 and/or TP53 knockdown to facilitate anchorage-independent proliferation of HCECs. On the other hand, only 5 out of 362 random shRNAs enhanced anchorage-independent growth. This study supports the hypothesis that multiple independent genes abrogate various pathways that precancerous cells acquire in order to progress. The study also provides interesting new insights into the role of tumor suppressor networks in contributing to the heterogeneity of somatic mutations detected in primary colorectal tumors.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.